BRCA1 & BRCA2 Germline Variants Are Enriched in MDS/AML and Portend Higher Average Mutational Burden

The homologous DNA repair pathway genes BRCA1 and BRCA2 are classically associated with increased susceptibility to hereditary breast and ovarian cancer due to increased vulnerability to double stranded DNA breaks (mutator phenotype). In addition to their role in breast/ovarian cancer, defects in these genes may predispose to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). For example, in large populations of breast cancer patients, those with inherited defects in homologous repair (HR) showed a propensity to therapy-related MDS and AML; however, a relationship between BRCA gene variants and spontaneous myeloid neoplasms has yet to be elucidated. Moreover, analyses are complicated by the large number of clinically uncharacterized single nucleotide variants (SNV) in BRCA gene loci.We thus evaluated the relationship between germline BRCA variants (GLVs) and the risk of adult MDS or AML. We applied next generation sequencing to a large cohort of patients (N =463) presenting with MDS (402) and AML (61). In these analyses, all mutations with a variant allele frequency of less than 30% were considered somatic. We then identified alterations known to be linked with breast/ovarian cancer development by linkage analyses. These mutations (n=2), along with missense mutations with an allele frequency <.001% and previously unknown mutations with a CADD score >10, were considered Tier-1 mutations (n=37). Tier 2 mutations were defined as missense mutations with a pop...

Source: Blood - November 21, 2018 Category: Hematology Authors: Williams, L., Kuzmanovic, T., Hirsch, C. M., Przychodzen, B. P., Saunthararajah, Y., Awada, H., Adema, V., Graham, A. C., Radivoyevitch, T., Carraway, H. E., Nazha, A., Sekeres, M. A., Maciejewski, J. P. Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster III Source Type: research